Process for producing cyclic compound

ABSTRACT

A process suitable for safely mass-producing, through a short step, cyclic compounds useful in medicines, agricultural chemicals, foods, cosmetics, and chemical products or as intermediates therefor. The process, which is for producing a compound represented by the formula:  
                 
 
{wherein Z represents an electron-attracting group; W represents optionally substituted ethylene or optionally substituted vinylene; R 3  represents hydrogen or an optionally substituted hydrocarbon group; and X represents a divalent group [provided that when W represents optionally substituted vinylene, then —X—CH 2 -Z is not —X 1 —X 2 —CH, -Z (wherein X 1  represents sulfur or optionally substituted nitrogen and X 2  represents optionally substituted ethylene)]} or a salt thereof, is characterized by subjecting a compound represented by the formula (II) or a salt thereof:  
                 
(wherein the symbols have the same meanings as the above) to a ring closure reaction in a solvent containing a carbonic diester.

TECHNICAL FIELD

The present invention relates to a process for producing cycliccompounds useful as medicines, agricultural chemicals, foods, cosmeticsand chemical products, or intermediates thereof.

BACKGROUND ART

Heretofore, several synthetic methods for cyclic compounds have beendescribed in literature, including, for example, (1) an intramolecularFriedel-Crafts Reaction in the case of cyclic ketone derivatives (JP-A57-192379, etc.), (2) a Dieckmann-type cyclization reaction of diesterderivatives, followed by reduction and dehydration reactions in the caseof cyclic acrylic acid derivatives (J. Chem. Res., Synop., (1987), (12),394-5, etc.), (3) an intramolecular Wittig Reaction in the case ofcyclic alkene derivatives (W098/55475, etc.) and others.

However, even though a variety of useful intermediates have beendescribed, for example, in J. Heterocyclic Chem., 31, 351-355 (1994),Heterocycles, 49, 215-232 (1998), J. Heterocyclic Chem., 33, 1909-1913(1996), etc., cyclic compounds (especially, cyclic compounds having 8-or more-membered ring) are still generally difficult to synthesize andcan be obtained only at low yields even if possible.

From the current situation as described above, it is desirable toestablish a convenient production method (i.e., a production methodwhich employs readily available low-cost raw materials, and reagentssuitable for large scale synthesis and having no disposal problems, andwhich comprises relatively short steps and is easier to carry out), ofcyclic compounds, especially cyclic alkene derivatives, which can beeasily converted to a variety of derivatives including, e.g., cyclicketone derivatives or cyclic acrylic acid derivatives, due to theircharacteristic chemical structure.

DISCLOSURE OF INVENTION

As a result of intensive studies, the present inventors found that acyclic alkene derivative can be produced inexpensively and convenientlyby using an activated methylene derivative as a reaction intermediateand by conducting a cyclization reaction in the presence of a carbonicdiester, and on the basis of this knowledge, after further studies,completed the present invention.

That is, the present invention provides

(1) A process for producing a compound represented by the formula:

[wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene, and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedcyclic ring; R³ is a hydrogen atom or an optionally substitutedhydrocarbon group; and X is a divalent group (preferably, a divalentgroup having 3 or more atoms in the straight-chain moiety thereof)(however, when W is an optionally substituted vinylene, —X—CH₂-Z is not—X¹—X²—CH₂-Z (wherein, X¹ is a sulfur atom or an optionally substitutednitrogen atom, X² is an optionally substituted ethylene))] or a saltthereof, which comprises subjecting a compound represented by theformula:

[wherein, each symbol has the same meaning described as above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester;

(2) The process according to the above-mentioned (1), wherein X is adivalent group having 1 to 12 atoms in the straight-chain moiety thereof(preferably, 3 to 12 atoms in the straight-chain moiety thereof);

(3) The process according to the above-mentioned (1), wherein Z is acarboxyl group which is esterified;

(4) The process according to the above-mentioned (1), wherein R³ is ahydrogen atom;

(5) The process according to the above-mentioned (1), which comprisesthe reaction being carried out in the presence of a base;

(6) The process according to the above-mentioned (5), wherein the baseis an alcoholate;

(7) The process for producing a compound represented by the formula:

[wherein, Z is an electron-withdrawing group; R¹ and R² each are ahydrogen atom, a halogen atom, an optionally substituted amino group, anoptionally substituted hydroxy group, an optionally substituted thiolgroup, an optionally substituted hydrocarbon group, or an optionallysubstituted heterocyclic; R¹ and R² may be bound to each other to forman optionally substituted ring; R³ is a hydrogen atom or an optionallysubstituted hydrocarbon group; the combined line of a broken line and asolid line is a single bond or a double bond; and X is a divalent group(preferably, a divalent group having 3 or more atoms in thestraight-chain moiety thereof) (however, when the combined line of abroken line and a solid line is a double bond, —X—CH₂-Z is not—X¹—X²—CH₂-Z (wherein, X¹ is a sulfur atom or an optionally substitutednitrogen atom, X² is an optionally substituted ethylene))] or a saltthereof, which comprises subjecting a compound represented by theformula:

[wherein, each symbol has the same meaning described as above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester;

(8) The process according to the above-mentioned (7), wherein X is adivalent group having 1 to 12 atoms in the straight-chain moiety thereof(preferably, 3 to 12 atoms in the straight-chain moiety thereof);

(9) The process according to the above-mentioned (7), wherein Z is acarboxyl group which is esterified;

(10) The process according to the above-mentioned (7), wherein R³ is ahydrogen atom;

(11) The process according to the above-mentioned (7), which comprisesthe reaction being carried out in the presence of a base;

(12) The process according to the above-mentioned (11), wherein the baseis an alcoholate;

(13) The process for producing a compound represented by the formula:

[wherein, Z is an electron-withdrawing group; R³ is a hydrogen atom oran optionally substituted hydrocarbon group; the combined line of abroken line and a solid line is a single bond or a double bond; ring Ais an optionally substituted ring; and X is a divalent group(preferably, a divalent group having 3 or more atoms in thestraight-chain moiety thereof) (however, when the ring A is anoptionally substituted benzene ring and the combined line of a brokenline and a solid line is a double bond, —X—CH₃-Z is not —X¹—X²—CH₂-Z(wherein, X¹ is sulfur atom or an optionally substituted nitrogen atom;X² is an optionally substituted ethylene))] or a salt thereof, whichcomprises subjecting a compound represented by the formula:

[wherein, each symbol has the same meaning described as above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester;

(14) The process according to the above-mentioned (13), wherein X is adivalent group having 1 to 12 atoms in the straight-chain moiety thereof(preferably, 3 to 12 atoms in the straight-chain moiety thereof);

(15) The process according to the above-mentioned (13), wherein Z is acarboxyl group which is esterified;

(16) The process according to the above-mentioned (13), wherein R³ is ahydrogen atom;

(17) The process according to the above-mentioned (13), which comprisesthe reaction being carried out in the presence of a base;

(18) The process according to the above-mentioned (17), wherein the baseis an alcoholate;

(19) The compound represented by the formula:

[wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene, and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedring; R³ is a hydrogen atom or an optionally substituted hydrocarbongroup; and X″ is a divalent group having 4 or more atoms in thestraight-chain moiety thereof] or a salt thereof;

(20) The compound according to the above-mentioned (19), wherein X″ is adivalent group having 4 to 6 atoms in the straight-chain moiety thereof;

(21) The compound according to the above-mentioned (19), wherein Z is acarboxyl group which is esterified;

(22) The compound according to the above-mentioned (19), wherein R³ is ahydrogen atom;

(23) The compound represented by the formula:

[wherein, Z is an electron-withdrawing group; R¹ and R² each are ahydrogen atom, a halogen atom, an optionally substituted amino group, anoptionally substituted hydroxy group, an optionally substituted thiolgroup, an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group; R¹ and R² may be bound to each other toform an optionally substituted ring; R³ is a hydrogen atom or anoptionally substituted hydrocarbon group; the combined line of a brokenline and a solid line is a single bond or a double bond; and X″ is adivalent group having 4 or more atoms in the straight-chain moietythereof] or a salt thereof;

(24) The compound according to the above-mentioned (23), wherein X″ is adivalent group having 4 to 6 atoms in the straight-chain moiety thereof;

(25) The compound according to the above-mentioned (23), wherein Z is acarboxyl group which is esterified;

(26) The compound according to the above-mentioned (23), wherein R³ is ahydrogen atom;

(27) The compound represented by the formula:

[wherein, Z is an electron-withdrawing group; R³ is a hydrogen atom oran optionally substituted hydrocarbon group; the combined line of abroken line and a solid line is a single bond or a double bond; ring Ais an optionally substituted ring; and X″ is a divalent group having 4or more atoms in the straight-chain moiety thereof] or a salt thereof;

(28) The compound according to the above-mentioned (27), wherein X″ is adivalent group having 4 to 6 atoms in the straight-chain moiety thereof;

(29) The compound according to the above-mentioned (27), wherein Z is acarboxyl group which is esterified; and

(30) The compound according to the above-mentioned (27), wherein R³ is ahydrogen atom; and the like.

Examples of “electron-withdrawing group” used in the presentspecification include (i) a carboxyl group which may be optionallyesterified or amidated, (ii) a group represented by the formula: —(CO)R⁴(wherein, R⁴ is a hydrogen atom or an optionally substituted hydrocarbongroup), (iii) nitrile group, (iv) nitro group, (v) a group representedby the formula: —(SO_(m))R⁵ ( wherein, m is an integer of 1 or 2, and R⁵is an optionally substituted hydrocarbon group), (vi) a grouprepresented by the formula: —PR⁶R⁷ (wherein, R⁶ and R⁷ each are anoptionally substituted hydrocarbon group), (vii) a group represented bythe formula: —(PO)(OR⁸)(OR⁹) (wherein, R⁸ and R⁹ each are a hydrogen oran optionally substituted hydrocarbon group), (viii) an optionallysubstituted aryl group, (ix) an optionally substituted alkenyl group,(x) a halogen atom ( e.g., fluorine, chlorine, bromine, iodine, etc.)and (xi) a nitroso group and the like, preferably, a carboxyl groupwhich may be optionally esterified or amidated, a group represented bythe formula: —(CO)R⁴, nitrile group, nitro group, a group represented bythe formula: —(SO_(m))R⁵, a group represented by the formula: —PR⁶R⁻, agroup represented by the formula: —(PO)(OR⁶)(OR⁹), more preferably, acarboxyl group which is esterified (e.g., a carboxyl group which isesterified by a C₁₋₄ alkyl such as methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, etc.) and the like.

The “carboxyl group which is esterified” in the “carboxyl group whichmay be optionally esterified or amidated” of (i) above include a grouprepresented by the formula: —(CO)OR¹⁰ (wherein, R¹⁰ is an optionallysubstituted hydrocarbon group), while the “carboxyl group which isamidated” include a group represented by the formula: —(CO)NR¹¹R¹²(wherein, R¹¹ and R¹² are, respectively, a hydrogen atom or anoptionally substituted hydrocarbon group, and R¹¹ and R¹² may be boundto each other to form a 5- to 7-membered (preferably, 5- to 6-membered)cyclic amino group together with a neighboring nitrogen atom (e.g.,tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.)).

Further, in the formula of (vi) or (vii) above, R⁶ and R⁷, or R⁸ and R⁹may be bound to each other to form, for example, a lower (C₂₋₆) alkylene(e.g., dimethylene, trimethylene, tetramethylene, etc.), a lower (C₂₋₆)alkenylene (e.g., —CH, —CH═CH—, —CH₂—CH₂—CH═CH—, —CH₂—CH═CH—CH₂ —,etc.), or a lower (C₄₋₆) alkadienylene (e.g., —CH═CH—CH═CH—, etc.),etc., preferably, a lower (C₁₋₆) alkylene, more preferably, a lower(C₁₋₄) alkylene, and these divalent groups may have optionallysubstituent groups including, for example, hydroxy group, a halogenatom, a C₁₋₄ alkyl, a C₁₋₄ alkoxy, etc.

Examples of the “aryl group” in the optionally substituted aryl group of(viii) above include, for example, C₆₋₁₄ aryl groups such as phenyl,naphthyl, etc., preferably, C₆₋₁₀ aryl groups, etc., more preferably,phenyl, etc. The aryl group may have 1 to 3 substituent groups similarto those of the “optionally substituted hydrocarbon group” describedbelow.

The “alkenyl groups” in the optionally substituted alkenyl group of (ix)above include, for example, alkenyl groups having 2 to 10 carbon atomssuch as vinyl, allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., and the like,preferably, lower (C₂₋₆) alkenyl groups, etc., more preferably, vinyl,etc. The alkenyl group may have 1 to 3 substituent groups similar tothose of the “optionally substituted hydrocarbon group” described below.

Examples of the “hydrocarbon group” in the “optionally substitutedhydrocarbon group” used in the present specification include;

(1) an alkyl group (e.g., C₁₋₁₀ alkyl groups such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,preferably, lower (C₁₋₆) alkyl groups, etc.);

(2) a cycloalkyl group. (e.g., C₃₋₇ cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike);

(3) an alkenyl group (e.g., alkenyl groups having 2 to 10 carbon atomssuch as vinyl, allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably,lower (C₂₋₆) alkenyl groups, etc.);

(4) a cycloalkenyl group (e.g., cycloalkenyl groups having 3 to 7 carbonatoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl and the like);

(5) an alkynyl group (e.g., alkynyl groups having 2 to 10 carbon atomssuch as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl,3-hexynyl, etc., preferably, lower (C₂₋₆) alkynyl groups and the like);

(6) an aryl group (e.g., C₆₋₁₄ aryl groups such as phenyl, naphthyl,etc., preferably, C₆₋₁₀ aryl groups, more preferably, phenyl, etc.); and

(7) an aralkyl group (e.g., phenyl-C₁₋₄ alkyl groups (e.g., benzyl,phenethyl, etc.) and the like). The examples of the hydrocarbon groupsare preferably, an alkyl group, more preferably, a C₁₋₄ alkyl group suchas methyl, ethyl, etc., and particularly preferably, methyl.

Said hydrocarbon group may have substituent groups, including, forexample, a halogen atom (e.g., fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy, an optionally substituted thiol group(e.g., thiol, C₁₋₄ alkylthio, etc.), an optionally substituted aminogroup (e.g., amino, monoC₁₋₄ alkylamino, diC₁₋₄alkylamino, 5- to6-membered cyclic amino groups such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole and thelike), a carboxyl group which may be optionally esterified or amidated(e.g., carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, monoC₁₋₄alkylcarbamoyl,diC₁₋₄ alkylcarbamoyl, etc.), a C₁₋₄ alkyl group which may be optionallysubstituted with halogen atoms or C₁₋₄ alkoxy groups (e.g.,trifluoromethyl, methyl, ethyl, etc.), a C₁₋₄ alkoxy group which may beoptionally substituted with halogen atoms or C₁₋₄ alkoxy groups (e.g.,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, aC₁₋₄ alkanoyl group (e.g., acetyl, propionyl, etc.), a C₁₋₄alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), and aC₁₋₄ alkylsulfinyl (e.g., methanesulfinyl, ethanesulfinyl, etc.). Thenumber of the substituent groups is preferably 1 to 3.

In the formula above, the “ethylene” and the “vinylene” in the“optionally substituted ethylene” and the “optionally substitutedvinylene” represented by W include divalent groups represented by theformula: —CH₂—CH₂— and the formula: —CH═CH—. These divalent groups mayhave substituent groups at any position where substitution is possible,and examples thereof include substituent groups similar to those of “ahalogen atom”, “an optionally substituted amino group”, “an optionallysubstituted hydroxy group”, “an optionally substituted thiol group”, “anoptionally substituted hydrocarbon group” and “an optionally substitutedheterocyclic group” represented by R¹ and R² described below. When theethylene or the vinylene has two substituent groups, the substituentgroups may be bound to each other to form an optionally substitutedring. Further, R¹ and R² may be bound to each other to form anoptionally substituted ring. Here, examples of the optionallysubstituted ring are those similar to an optionally substituted ring asring A described below (preferably, an optionally substituted benzenering and the like).

Examples of the “halogen atom” represented by R¹ and R² in the formulaabove include fluorine, chlorine, bromine, iodine, etc.

Examples of the “optionally substituted amino group” represented by R¹and R² in the formula above include amino groups which may be optionallysubstituted by the “optionally substituted hydrocarbon groups” mentionedabove. The number of substituent groups may be any of 0 to 2. When twosubstituent groups are present, the two substituent groups may be thesame or different. Further, the two substituent groups may be bound toeach other to form a 5- to 7-membered (preferably, 5- to 6-membered)cyclic amino group together with neighboring nitrogen atoms (e.g.,tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.).

Examples of the “optionally substituted hydroxy group” represented by R¹and R² in the formula above include hydroxy groups which may beoptionally substituted by the “optionally substituted hydrocarbongroups” mentioned above.

Examples of “the optionally substituted thiol group” represented by R¹and R² in the formula above include thiol groups which may be optionallysubstituted by the “optionally substituted hydrocarbon groups” mentionedabove.

In the formula above, examples of the “heterocyclic ring” in the“optionally substituted heterocyclic group” represented by R¹ and R²,include 5- to 7-memberd aromatic heterocyclic rings and saturated orunsaturated non-aromatic heterocyclic rings (aliphatic heterocyclicrings), containing at least one (preferably, 1 to 4, more preferably 1to 2) hetero atoms of 1 to 3 (preferably, 1 to 2) hetero atoms selectedfrom the group consisting of oxygen atom, sulfur atom, nitrogen atom andother atoms.

Herein, examples of the “aromatic heterocyclic ring” include 5- to6-membered aromatic monocyclic heterocyclic rings (e.g., furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, etc.). Examples of the“non-aromatic heterocyclic ring” include 5- to 7-membered (preferably,5- to 6-membered) saturated or unsaturated (preferably, saturated)non-aromatic heterocyclic rings (aliphatic heterocyclic rings) such aspyrrolidine, tetrahydrofuran, thiolane, piperidine, tetrahydropyran,morpholine, thiomorpholine, piperazine, pyran, etc., and 5- to6-membered non-aromatic heterocyclic rings wherein all or a part ofdouble bonds in the afore-mentioned aromatic monocyclic heterocyclicrings are saturated. The heterocyclic ring is preferably a 5- to6-membered aromatic ring, and more preferably furan, thiophene, pyrrole,or pyridine (preferably a 6-membered ring).

Examples of substituent groups which may be possessed by theheterocyclic ring include substituent groups exemplified as thesubstituent groups on the “optionally substituted hydrocarbon group”described above, and the number of the substituent groups is 1 to 3.

In the formula above, Z is preferably an esterified carboxyl group, R³is preferably a hydrogen atom, and RI and R² each is preferably ahydrogen atom or an optionally substituted hydrocarbon group, morepreferably a hydrogen atom, and it is also preferable that R¹ and R² arebound to each other to form an optionally substituted benzene ring.

The substituent groups which may be possessed by the “optionallysubstituted benzene ring” used in the present specification includesubstituent groups exemplified as the substituent groups on the“optionally substituted hydrocarbon group” described above; theafore-described “optionally substituted aryl groups”, which may be boundvia a spacer (e.g., a divalent group having 1 to 4 atoms in thestraight-chain moiety thereof) (preferably, afore-described “optionallysubstituted aryl groups which is directly bound), and particularlypreferably electron-donating groups. The number of the substituentgroups is 1 to 4.

Examples of the “spacer” are —(CH₂)_(a)— [a is an integer of 1 to 4(preferably, an integer of 1 to 2)], —(CH₂)_(b)—X′— [b is an integer of0 to 3 (preferably, an integer of 0 to 1), X′ is an optionallysubstituted imino group (e.g., imino groups which may be substitutedwith lower (C₁₋₆) alkyl, lower (C₃₋₇) cycloalkyl, formyl, lower (C₂₋₇)alkanoyl, lower (C₁₋₆) alkoxy-carbonyl etc.), a carbonyl group, anoxygen atom or an optionally oxidized sulfur atom (e.g., —S(O)_(n)— (nis an integer of 0 to 2))], —CH═CH—, —C≡C—, —CO—NH—, —SO₂—NH— etc.(preferably —(CH₂)_(b)—X′—, more preferably —CH₂—O—). These groups maybe bound to the “optionally substituted benzene ring” via-either theright or left bond, but they are bound to the “optionally substitutedbenzene ring” preferably via the right bond.

Examples of the ring formed by binding R¹ and R² and the “optionallysubstituted ring” represented by A in the formula above include 5- to7-membered (preferably, 5- to 6-membered) saturated or unsaturatedalicyclic hydrocarbons such as C₅₋₇ cycloalkanes (e.g., cyclopentane,cyclohexane, cycloheptane, etc.), C₅₋₇ cycloalkenes (e.g.,1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 2-cylcohexene,3-cylcohexene, etc.), and C₅₋₆ cycloalkadienes (e.g.,2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene, etc); 6- to14-membered aromatic hydrocarbons such as benzene, naphthalene, azulene,acenaphthylene, etc.; and 5- to 7-memberd aromatic heterocyclic ringsand saturated or unsaturated non-aromatic heterocyclic rings (aliphaticheterocyclic rings) containing at least one (preferably, 1 to 4, morepreferably 1 to 2) hetero atoms of 1 to 3 (preferably, 1 to 2) heteroatoms selected from the group consisting of oxygen atom, sulfur atom,nitrogen atom and other atoms.

Examples of the “aromatic heterocyclic ring” include 5- to 6-memberedaromatic monocyclic heterocyclic rings (e.g., furan, thiophene, pyrrole,oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3-triazole, pyridine,pyridazine, pyrimidine, pyrazine, etc.), and examples of the“non-aromatic heterocyclic ring” include 5- to 7-membered (preferably 5-to 6-membered) saturated or unsaturated non-aromatic monocyclicheterocyclic rings (aliphatic heterocyclic rings) such as pyrrolidine,tetrahydrofuran, thiolane, piperidine, morpholine, thiomorpholine,tetrahydropyran, piperazine, pyran etc., or 5- to 6-memberednon-aromatic heterocyclic rings wherein all or a part of the doublebonds in the afore-described aromatic monocyclic heterocyclic rings aresaturated.

Further, the ring formed by binding R¹ and R², and the “optionallysubstituted ring” represented by A in the formula above may form a fusedring wherein 2 to 3 (preferably, 2) monocyclic rings described above arecondensed. Preferable examples of the fused ring include fused rings oftwo same or different heterocyclic rings (preferably, one heterocyclicring and one aromatic heterocyclic ring, more preferably, two same ordifferent aromatic heterocyclic rings); and fused rings of aheterocyclic ring and a homocyclic ring (preferably, a heterocyclic ringand a benzene ring, more preferably, an aromatic heterocyclic ring and abenzene ring). Specific examples of the fused ring include indole,benzothiophene, benzofuran, benzimidazole, imidazo[1,2-a]pyridine,quinoline, isoquinoline, cinnoline, etc.

The ring formed by binding R¹ and R², and the “optionally substitutedring” represented by A in the formula above is preferably a 5- to6-membered aromatic ring, more preferably benzene, furan, thiophene,pyrrole, or pyridine (preferably, a 6-membered ring), and particularlypreferably benzene.

The ring formed by binding R¹ and R^(2,) and the ring A may havesubstituent groups, examples thereof include those similar to thesubstituent groups which may be possessed by the “benzene ring” in the“optionally substituted benzene ring” described above. 1 to 3 same ordifferent substituent groups may substitute at any position of the ringwhere substitution is possible.

In the formula above, the “divalent group” represented by X ispreferably a divalent group having 3 or more atoms in the straight-chainmoiety thereof, and, for example, any group may be employed whicheverring B in the following formula can form a 5- to 16-membered ring(preferably 5- to 12-membered ring, more preferably 7- to 10-memberedring, particularly preferably 8- to 10-membered ring): the formula

the formula

or the formula

That is, X may be any of divalent groups having 1 to 12 atoms in thestraight-chain moiety thereof (preferably 1 to 8, more preferably 3 to6, and particularly preferably 4 to 6), and specific examples of thedivalent group include

(1) —(CH₂)_(a1)— (a1 is an integer of 1 to 12, preferably 3 to 12),—(CH₂)_(a2)—(CH═CH)—(CH₂)_(a3)— (a2 and a3 each are the same ordifferent integer of 0 to 10. But, the sum of a2 and a3 is 10 or lower,preferably 1 to 10), —(CH₂)_(a4)—(CH═C═CH)—(CH₂)_(a5)— (a4 and a5 eachare the same or different integer of 0 to 9. But, the sum of a4 and a5is 9 or lower),

(2) —(CH₂)_(b1)—Y—(CH₂)_(b2)— (b1 and b2 each are the same or differentinteger of 0 to 11. But, the sum of b1 and b2 is 11 or lower, preferably2 to 11. Y is O, S, or NH), —(CH₂)_(b3)—Y—(CH₂)_(b4)—(CH═CH)—(CH₂)_(b5)—or —(CH₂)_(b5)—(CH═CH)—(CH₂)_(b4)—Y—(CH₂)_(b3)— (b3, b4 and b5 are,respectively, the same or different integer of 0 to 9. But, the sum ofb3, b4 and b5 is 9 or less. Y is O, S, or NH),—(CH₂)_(b6)—Y—(CH₂)_(b7)—(CH═C═CH)—(CH₂)_(b8)— or—(CH₂)_(b8)—(CH═C═CH)—(CH₂)_(b7)—Y—(CH₂)_(b6)— (b6, b7, and b8 are,respectively, the same or different integer of 0 to 8. But, the sum ofb6, b7 and b8 is 8 or less. Y is O, S, or NH),

(3) —(CH₂)_(c1)—(N═CH)—(CH₂)_(c2)— (c1 and c2 are, respectively, thesame or different integer of 0 to 10. But, the sum of c1 and c2 is 10 orless, preferably 1 to 10),—(CH₂)_(c3)—(N═CH)—(CH₂)_(c4)—(CH═CH)—(CH₂)_(c5)— or—(CH₂)_(c5)—(CH═CH)—(CH₂)_(c4)—(N═CH)—(CH₂)_(c2)— (c3, c4 and c5 are,respectively, the same or different integer of 0 to 8. But, the sum ofc3, c4 and c5 is 8 or less),—(CH₂)_(c6)—(N═CH)—(CH₂)_(c7)—(CH═C═CH)—(CH₂)_(c8)— or—(CH₂)_(c8)—(CH═C═CH)—(CH₂)_(c7)—(N═CH)—(CH₂)_(c6)— (c6, c7 and c8 are,respectively, the same or different integer of 0 to 7. But, the sum ofc6, c7 and c8 is 7 or less),

(4) —(CH₂)_(d1)—(CH═N)—(CH₂)_(d2)— (d1 and d2 are, respectively the sameor different integer of 0 to 10. But, the sum of d1 and d2 is 10 orlower, preferably 1 to 10),—(CH₂)_(d3)—(CH═N)—(CH₂)_(d4)—(CH═CH)—(CH₂)_(d5)— or—(CH₂)_(d5)—(CH═CH)—(CH₂)_(d4)—(CH═N)—(CH₂)_(d3)— (d3, d4 and d5 are,respectively, the same or different integer of 0 to 8. But, the sum ofd3, d4 and d5 is 8 or less),—(CH₂)_(d6)—(CH═N)—(CH₂)_(d7)—(CH═C═CH)—(CH₂)_(d8)— or—(CH₂)_(d8)—(CH═C═CH)—(CH₂)_(d7)—(CH═N)—(CH₂)_(d6)— (d6, d7 and d8 are,respectively, the same or different integer of 0 to 7. But, the sum ofd6, d7 and d8 is 7 or less),

(5) —(CH₂)_(e1)—(N═N)—(CH₂)_(e2)— (e1 and e2 are, respectively, the sameor different integer of 0 to 10. But, the sum of e1 and e2 is 10 orless, preferably 1 to 10),—(CH₂)_(e3)—(N═N)—(CH₂)_(e4)—(CH═CH)—(CH₂)_(e5)— or—(CH₂)_(e5)—(CH═CH)—(CH₂)_(e4)—(N═N)—(CH₂)_(e3)— (e3, e4 and e5 are,respectively, the same or different integer of 0 to 8. But, the sum ofe3, e4 and e5 is 8 or less),—(CH₂)_(e6)—(N═N)—(CH₂)_(e7)—(CH═C═CH)—(CH₂)_(e8)— or—(CH₂)_(e8)—(CH═C═CH)—(CH₂)_(e7)—(N═N)—(CH₂)_(e6)— (e6, e7 and e8 are,respectively, the same or different integer of 0 to 7. But, the sum ofe6, e7 and e8 is 7 or less),

(6) —(CH₂)_(f1)—Y—(CH₂)_(f2)—(N═CH)—(CH₂)_(f3)— (f1, f2 and f3 are,respectively, the same or different integer of 0 to 9. But, the sum off1, f2 and f3 is 9 or less. Y is O, S or NH),—(CH₂)_(f3)—(N═CH)—(CH₂)_(f2)—Y—(CH₂)_(f1)— (f1, f2 and f3 are,respectively, the same or different integer of 0 to 9. But, the sum off1, f2 and f3 is 9 or less, Y is O, S or NH),—(CH₂)_(f4)—(CH═CH)—(CH₂)_(f5)—Y—(CH₂)_(f6)—(N═CH)—(CH₂)_(f7)— (f4, f5,f6 and f7 are, respectively, the same or different integer of o to 7.But, the sum of f4, f5, f6 and f7 is 7 or less. Y is O, S or NH),—(CH₂)_(f8)—Y—(CH₂)_(f9)—(CH═CH)—(CH₂)_(f10)—(N═CH)—(CH₂)_(f11)— (f8,f9, f10 and f11 are, respectively, the same or different integer of 0 to7. But, the sum of f8, f9, f10 and f11 is 7 or less. Y is O, S or NH),—(CH₂)_(f12)—Y—(CH₂)_(f12)—(N═CH)—(CH₂)_(f14)—(CH═CH)—(CH₂)_(f15)— (f12,f13, f14 and f15 are, respectively, the same or different integer of 0to 7. But, the sum of f12, f13, f14 and f15 is 7 or less),—(CH₂)_(f7)—(N═CH)—(CH₂)_(f6)—Y—(CH₂)_(f5)—(CH═CH)—(CH₂)_(f4)— (f4, f5,f6 and f7 are, respectively, the same or different integer of 0 to 7.But, the sum of f4, f5, f6 and f7 is 7 or less. Y is O, S or NH),—(CH₂)_(f11)—(N═CH)—(CH₂)_(f10)—(CH═CH)—(CH₂)_(f9)—Y—(CH₂)_(f8)— (f8,f9, f10 and f11 are, respectively, the same or different integer of 0 to7. But, the sum of f8, f9, f10 and f11 is 7 or less. Y is O, S or NH),—(CH₂)_(f15)—(CH═CH)—(CH₂)_(f14)—(N═CH)—(CH₂)_(f13)—Y—(CH₂)_(f12)— (f12,f13, f14 and f15 are, respectively, the same or different integer of 0to 7. But,the sum of f12, f13, f14 and f15 is 7 or less),

(7) —(CH₂)_(g1)—Y—(CH₂)_(g2)—(CH═N)—(CH₂)_(g3)— (g1, g2 and g3 are,respectively the same or different integer of 0 to 9. But, the sum ofg1, g2 and g3 is 9 or less. Y is O, S or NH), —(CH₂)_(g3)—(CH═N)—(CH₂)_(g2)—Y—(CH₂)_(g1)— (g1, g2 and g3 are, respectively, thesame or different integer of 0 to 9. But, the sum of g1, g2 and g3 is 9or less. Y is O, S or NH),—(CH₂)_(g4)—(CH═CH)—(CH₂)_(g5)—Y—(CH₂)_(g6)—(CH═N)—(CH₂)_(g7)— (g4, g5,g6 and g7 are, respectively, the same or different integer of o to 7.But, the sum of g4, g5, g6 and g7 is 7 or less. Y is O, S or NH),—(CH₂)_(g8)—Y—(CH₂)_(g9)—(CH═CH)—(CH₂)_(g10)—(CH═N)—(CH₂)_(g11)— (g8,g9, g10 and g11 are, respectively, the same or different integer of 0 to7. But, the sum of g8, g9, g10 and g11 is 7 or less. Y is O, S or NH),—(CH₂)_(g12)—Y—(CH₂)_(g13)—(CH═N)—(CH₂)_(g14)—(CH═CH)—(CH₂)_(g15)— (g12,g13, g14 and g15 are, respectively, the same or different integer of 0to 7. But, the sum of g12, g13, g14 and g15 is 7 or less),—(CH₂)_(g7)—(CH═N)—(CH₂)_(g6)—Y—(CH₂)_(g5)—(CH═CH)—(CH₂)_(g4)— (g4, g5,g6 and g7 are, respectively, the same or different integer of 0 to 7.But, the sum of g4, g5, g6 and g7 is 7 or less. Y is O, S or NH),—(CH₂)_(g11)—(CH═N)—(CH₂)_(g10)—(CH═CH)—(CH₂)_(g9)—Y—(CH₂)_(g8)— (g8,g9, g10 and g11 are, respectively, the same or different integer of 0 to7. But, the sum of g8, g9, g10 and g11 is 7 or less. Y is O, S or NH),—(CH₂)_(g15)—(CH═CH)—(CH₂)_(g14)—(CH═N)—(CH₂)_(g13)—Y—(CH₂)_(g12)— (g12,g13, g14 and g15 are, respectively, the same or different integer of 0to 7. But, the sum of g12, g13, g14 and g15 is 7 or less),

(8) —(CH₂)_(h1)—Y—(CH₂)_(h2)—(N═N)—(CH₂)_(h3)— (h1, h2 and h3 are,respectively the same or different integer of 0 to 9. But, the sum ofh1, h2 and h3 is 9 or less. Y is O, S or NH),—(CH₂)_(h3)—(N═N)—(CH₂)_(h2)—Y—(CH₂)_(h1)— (h1, h2 and h3 are,respectively, the same of different integer of 0 to 9. But, the sum ofh1, h2 and h3 is 9 or less. Y is O, S or NH),—(CH₂)_(h4)—(CH═CH)—(CH₂)_(h5)—Y—(CH₂)_(h6)—(N═N)—(CH₂)_(h7)— (h4, h5,h6 and h7 are, respectively, the same or different integer of 0 to 7.But, the sum of h4, h5, h6 and h7 is 7 or less. Y is O, S or NH),—(CH₂)_(h8)—Y—(CH₂)_(h9)—(CH═CH)—(CH₂)_(h10)—(N═N)—(CH₂)_(h11)— (h8, h9,h10 and h11 are, respectively, the same or different integer of 0 to 7.But, the sum of h8, h9, h10 and h11 is 7 or less. Y is O, S or NH),—(CH₂)_(h12)—Y—(CH₂)_(h13)—(N═N)—(CH₂)h₁₄—(CH═CH)—(CH₂)_(h15)— (h12,h13, h14 and h15 are, respectively, the same or different integer of 0to 7. But, the sum of h12, h13, h14 and h15 is 7 or less),—(CH₂)_(h7)—(N═N)—(CH₂)_(h6)—Y—(CH₂)_(h5)—(CH═CH)—(CH₂)_(h4)— (h4, h5,h6 and h7 are, respectively, the same or different integer of 0 to7.But, the sum of h4, h5, h6 and h7 is 7 or less. Y is O, S or NH),—(CH₂)_(h11)—(N═N)—(CH₂)_(h10)—(CH═CH)—(CH₂)_(h9)—Y—(CH₂)_(h8)— (h8, h9,h10 and h11 are, respectively the same or different integer of 0 to 7.But, the sum of h8, h9, h10 and h11 is 7 or less. Y is O, S or NH),—(CH₂)_(h15)—(CH═CH)—(CH₂)_(h14)—(N═N)—(CH₂)_(h13)—Y—(CH₂)_(h12)— (h12,h13, h14 and h15 are, respectively, the same or different integer of 0to 7. But, the sum of h12, h13, h14 and h15 is 7 or less),

(9) —(CH₂)_(j1)—Y¹—(CH₂)_(j2)—Y²—(CH₂)_(j3)— (j1, j2 and j3 are,respectively, the same or different integer of 0 to 10. But, the sum ofj1, j2 and j3 is 10 or less, preferably 1 to 10. Y¹ and Y² are,respectively, O, S or NH) ,—(CH₂)_(j4)—Y⁴—(CH₂)_(j5)—Y⁵—(CH₂)_(j6)—Y⁶—(CH₂)_(j7)— (j4, j5, j6 andj7 are, respectively, the same or different integer of 0 to 9. But, thesum of j4, j5, j6 and j7 is 9 or lower. Y⁴, Y⁵, Y⁶ and Y⁷ are,respectively, O, S or NH), and so on. Specific examples of the divalentgroup include —O—, —O—(CH₂)_(k1)— (k1 is an integer of 1 to 5,preferably 2 to 5), —O—CH═CH—, —O—CH₂—CH═CH—, —O—CH═CH—CH₂—,—(CH₂)_(k1)—O— (k1 is an integer of 1 to 5, preferably 2 to 5),—CH═CH—O—, —CH₂—CH═CH—O—, —CH═CH—CH₂—O—, —S—, —S—(CH₂)_(k2)— (k2 is aninteger of 1 to 5, preferably 2 to 5), —S—CH═CH—, —S—CH₂—CH═CH—,—S—CH═CH—CH₂—, —(CH₂)_(k1)—S— (k1 is an integer of 1 to 5, preferably 2to 5), —CH═CH—S—, —CH₂—CH═CH—S—, —CH═CH—CH₂—S—, —NH—, —NH—(CH₂)_(k2)—(k2 is an integer of 1 to 5, preferably 2 to 5), —NH—CH═CH—,—NH—CH₂—CH═CH—, —NH—CH═CH—CH₂—, —(CH₂)_(k1)‘NH— (k1 is an integer of 1to 5, preferably 2 to 5), —CH═CH—NH—, —CH₂—CH═CH—NH—, —CH═CH—CH₂—NH—,—(CH₂)_(k2)— (k2 is an integer of 1 to 5, preferably 2 to 5), —CH═CH—,—CH₂—CH═CH—, —CH═CH—CH₂—, —N═CH—, —CH═N—, —N═N—, —CH₂—N═CH—, —CH₂—CH═N—,—CH₂—N═N—, —N═CH—CH₂—, —CH═N—CH₂—, —N═N—CH₂— etc., and preferableexamples include —O—(CH₂)_(k1)— (k1 is an integer of 1 to 5, preferably2 to 5, more preferably 3 to 5), —S—(CH₂)_(k2)— (k2 is an integer of 1to 5, preferably 2 to 5, more preferably 3 to 5), —NH—(CH₂)_(k2)— (k2 isan integer of 1 to 5, preferably 2 to 5, more preferably 3 to 5),—(CH₂)_(k2)— (k2 is an integer of 1 to 5, preferably 2 to 5, morepreferably 3 to 5), —(CH₂)_(k1)—O— (k1 is an integer of 1 to 5,preferably 2 to 5, more preferably 3 to 5), —(CH₂)_(k1)—S—(k1 is aninteger of 1 to 5, preferably 2 to 5, more preferably 3 to 5), and—(CH₂)_(k1)—NH— (k1 is an integer of 1 to 5, preferably 2 to 5, morepreferably 3 to 5), and more preferable examples are —O—(CH₂)₂—,—O—(CH₂)₃—, —O—(CH₂)₄—, —O—(CH₂)₅—, —S—(CH₂)₃—, —S—(CH₂ )₄—, —S—(CH₂)₅—,—NH—(CH₂)₃—, —NH—(CH₂)₄—, —NH—(CH₂)₅— and the like.

The divalent group may have substituent groups, and said substituentgroups may be any group which can be bound to the divalent group,including, for example, a halogen atom, an optionally substituted aminogroup, an optionally substituted hydroxy group, an optionallysubstituted thiol group, an optionally substituted hydrocarbon group andan optionally substituted heterocyclic group exemplified as R¹ and R².Further, the substituent groups may be bound to each other to form aring with the divalent group, and such rings include those exemplifiedas the rings formed by binding R¹ and R^(2.) Further, when an atomconstituting the straight chain moiety is a sulfur atom in the “divalentgroup” represented by X above, the sulfur atom may be oxidized, and maybe any of —S—, —SO— or —SO₂—.

Further, R¹ and a substituent group on X or R² and R³ may be bound toeach other to form an optionally substituted ring, and examples of suchring include those exemplified as the optionally substituted ringsformed by binding R¹ and R². When R¹ and a substituent group on X arebound to each other to form an optionally substituted ring, asubstituent group on the first to third (preferably the first to second,more preferably the first) atom in the straight chain moiety of X boundto the ethylene or vinylene is preferably bound to R¹.

Alternatively, a substituent group on the “ethylene” or “vinylene” ofthe “optionally substituted ethylene” or “optionally substitutedvinylene” represented by W may be bound to a substituent group of X orR³ to form an optionally substituted ring, and examples of such ringinclude those exemplified as the optionally substituted rings formed bybinding R¹ and R². When a substituent group of the “ethylene” or“vinylene” and a substituent group of X are bound to each other to forma ring, binding between a substituent on the first to third (preferablyfirst to second, more preferably first) atom in the straight chainmoiety of X bound to the ethylene or vinylene and a substituent group ofthe “ethylene” or “vinylene” is preferable.

In the formula above, the combined line of “broken line and solid line”indicates a single bond or a double bond (preferably double bond).

When a compound having a substituent group is a basic compound dependingon the kind of the substituent group exemplified above, the compound maybe converted to a salt thereof by using an acid according to usualmethods. Any acid may be used if the acid does not interfere with thereaction, and examples of the acid include inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,nitric acid, sulfamic acid etc., organic acids such as formic acid,acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaricacid, maleic acid, succinic acid, malic acid, p-toluenesulfonic acid,methanesulfonic acid, benzenesulfonic acid etc., and acidic amino acidssuch as aspartic acid, glutamic acid etc. When an obtained compound is asalt, the compound may be converted to a free base according to usualmethods.

Alternatively, when a compound having a substituent group is an acidiccompound depending on the kind of the substituent group exemplifiedabove, the compound may be converted to a salt thereof by using a baseaccording to usual methods. Any base may be used if the base does notinterfere with the reaction, and examples of such salts include saltswith inorganic bases, organic bases, basic amino acids, etc. Preferableexamples of the salt with an inorganic base include alkali metal saltssuch as sodium salt, potassium salt, etc.; alkali-earth metal salts suchas calcium salt, magnesium salt, etc.; and aluminum salt, ammonium salt,etc. Preferable examples of the salt with an organic base include saltswith trimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, etc. Preferable examples of the salt witha basic amino acid include salts with arginine, lysine, ornithine, etc.When an obtained compound is a salt, the compound may be converted to afree acid according to usual methods.

The reaction above-mentioned (1) is conducted, for example, under afollowing reaction condition.

The compound represented by the formula:

[wherein each symbol has the same meaning described above] or a saltthereof is produced by subjecting a compound represented by the formula:

[wherein each symbol has the same meaning described above] or a saltthereof to cyclization reaction in a solvent containing carbonicdiester.

The reaction above-mentioned (1) is preferably conducted in the presenceof a base, and examples of such base include metal hydride compounds(e.g., alkali metal hydrides such as sodium hydride, potassium hydride,etc.), metal hydrocarbons (e.g., compounds having direct chemical bondbetween alkali metal and C₁₋₄ alkyl group such as n-butyllithium, etc.),alcoholates (e.g., compounds in which a hydroxy hydrogen of C₁₋₄alcohols is replaced by a alkali metal such as sodium methoxide, sodiumethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide,potassium t-butoxide, lithium methoxide, lithium ethoxide, lithiumt-butoxide, etc.), alkali metal hydroxides (e.g., NaOH, KOH, etc.),basic carbonates (e.g., alkali metal salts of carbonate such as sodiumsalt, potassium salt, etc., or alkali-earth metal salts of carbonatesuch as calcium salt, magnesium salt, etc.), basic bicarbonates (e.g.,alkali metal salts of bicarbonate such as sodium salt, potassium salt,etc.), and organic bases (e.g., trimethylamine, triethylamine,diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo [5.4.0]-7-undecene,etc.), and preferably metal hydride compounds (e.g., sodium hydride,potassium hydride, etc.), alcoholates (e.g., NaOMe, NaOEt, t-BuONa,t-BuOK, etc.), particularly preferably alcoholates (e.g., NaOMe, NaOEt,t-BuONa, t-BuOK, etc.) is used.

The amount of base used for the reaction above-mentioned (1) is about0.1 to 100 equivalents, preferably 1 to 5 equivalents.

The reaction solvent may be any solvent if only it contains carbonicdiester, for example, a carbonic diester alone, a mixture of 2 or morecarbonic diesters or a mixed solvent of carbonic diesters and a solventexcept carbonic diesters.

The carbonic diester is a compound represented by the formula,Z″-O(CO)O-Z′, [wherein, Z″ and Z′ each are an optionally substitutedhydrocarbon group (preferably an optionally substituted alkyl group)].Preferable are carbonic diesters which are liquid at the reactiontemperature. In addition, Z″ and Z′ are preferably the same, andpreferable examples of the carbonic diester are dialkyl carbonates, anddi C₁₋₄ alkyl carbonates such as dimethyl carbonate, diethyl carbonateare preferably used.

The “solvent except carbonic diesters” used in combination with one ormore kinds of carbonic diesters may be any solvent if the solvent doesnot interfere with the reaction, and includes, for example, halogenatedsolvents (e.g., methylene chloride, dichloroethane, chloroform, etc.),aliphatic hydrocarbons (e.g., n-hexane, etc.), aromatic hydrocarbons(e.g., benzene, toluene, etc.), ethers (e.g., tetrahydrofuran (THF),diethylether, etc.), polar solvents (e.g., dimethylformamide (DMF),dimethylsulfoxide (DMSO), etc.), alcohols (e.g., methanol, ethanol,propanol, isopropanol, n-butanol, 2-methoxyethanol, etc.), formic acidesters (e.g., C₁₋₄ alkyl formate, etc.), and oxalic acid diesters (e.g.,di C₁₋₄ alkyl oxalate, etc), and preferably dimethylformamide (DMF),alcohols (e.g., methanol, ethanol, etc.) and so on.

The reaction may be conducted in an appropriate mixed solvent,preferably in a solvent containing carbonic diester (preferably,dimethyl carbonate or diethyl carbonate).

The reaction temperature is usually about −20 to 200° C., preferablyabout 10 to 100° C., and the reaction period is usually about 0.1 to 100hours, preferably about 0.5 to 50 hours.

The reaction above-mentioned (7) is conducted, for example, under afollowing reaction condition.

The compound represented by the formula:

[wherein each symbol has the same meaning described above] or a saltthereof is produced by subjecting a compound represented by the formula:

[wherein each symbol has the same meaning described above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester.

The reaction above-mentioned (7) may be conducted under a similarcondition to that for the reaction above-mentioned (1).

The reaction above-mentioned (13) is conducted for example under afollowing reaction condition.

The compound represented by the formula:

[wherein each symbol has the same meaning described above] or a saltthereof is produced by subjecting a compound represented by the formula:

[wherein each symbol has the same meaning described above] or a saltthereof to a cyclization reaction in a solvent containing a carbonicdiester.

The reaction above-mentioned (13) may be conducted under a conditionsimilar to those for the reaction above-mentioned (1).

Among the compounds represented by the following formula:

[wherein each symbol has the same meaning described above] or the saltthereof obtained in the reaction above-mentioned (1), the compoundsrepresented by the formula:

[wherein, Z is an electron-withdrawing group, W is an optionallysubstituted ethylene or an optionally substituted vinylene and when theethylene or vinylene has two substituent groups, said substituent groupsmay be bound to each other to form an optionally substituted ring, R³ isa hydrogen atom or an optionally substituted hydrocarbon group, and X″is a divalent group having 4 or more atoms in the straight-chain moietythereof (preferably, a divalent group having 4, 5 or 6 atoms in thestraight-chain moiety thereof)] or the salts thereof are novel compoundswhich have not been described in literature.

Further, the compounds represented by the formula:

[wherein, each symbol has the same meaning described above] or a saltthereof obtained in the reaction above-mentioned (1) are useful asmedicines, agricultural chemicals, foods, cosmetics and chemicals, orintermediates therefor. For example, from the compounds represented bythe formula:

[wherein each symbol has the same meaning described above] or the saltthereof obtained in the reaction above-mentioned (1), useful medicinessuch as an osteogenesis promoter, a Na—H exchange inhibitor, treatingagent for pollakiuria and incontinence of urine, edema treating agentand treating agent for central nervous system diseases can be producedaccording to the methods known in the art (e.g., methods described inJP-A 8-73476, W099/55690, JP-A 11-302267, JP-A 11-302270, W099/51242,etc.).

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described in more detail by thefollowing Reference Examples and Examples, which are not intended torestrict the present invention.

EXAMPLES Preparation of 2-alkoxybenzaldehyde Derivatives in General;Reference Example 1 Ethyl 4-(2-Formylphenoxy)butyrate

Ethyl 4-bromobutyrate (6.6ml) was added to a suspension of salicylaldehyde (5.0 g) and potassium carbonate (6.2 g) in DMF(15 ml), and themixture was stirred at 90° C. for 1 hour. The mixture was allowed tocool to room temperature, and neutralized with 1N hydrochloric acid.After extraction with ethyl acetate, the organic layer was washed withsaturated salt water, dried over anhydrous sodium sulfate, andconcentrated. The concentrate was purified by silica gel columnchromatography (n-hexane/ethyl acetate=4/1) and subsequent concentrationof the appropriate eluate gave colorless oil of Ethyl4-(2-formylphenoxy)butyrate (9.6 g, yield 99%).

¹H-NMR(CDCl₃, δ, 300 MHz): 1.27(3H, t, J=7.1 Hz), 2.14-2.23(2H, m),2.54(2H, t, J=7.2 Hz), 4.11-4.18(4H, m), 6.96-7.04(2H, m), 7.52(1H, dt,J=1.7, 7.1 Hz), 7.82(1H, dd, J=1.7, 7.7 Hz), 10.49(1H, s).

IR(neat, cm⁻¹): 1733, 1687, 1598, 1243.

Compounds below in [REFERENCE EXAMPLE 2] to [REFERENCE EXAMPLE 4] wereprepared according to a method similar to that of [REFERENCE EXAMPLE 1].

Reference Example 2 Ethyl 4-(4-Bromo-2-formyl phenoxy)butyrate

Colorless oil, yield 98%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.23(3H, t, J=7.1Hz), 2.11-2.20(2H, m), 2.50(2H, t, J=7.2 Hz), 4.08-4.16(4H, m), 6.85(1H,d, J=8.9), 7.58(1H, dd, J=8.9, 2.6 Hz), 7.88(1H, d, J=2.6 Hz), 10.37(1H, s) IR(neat, cm⁻¹): 1731, 1683, 1590, 1272.

Reference Example 3 Ethyl 4-(2-Formyl-4-methoxy phenoxy)butyrate

Colorless oil, yield 99%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.23(3H, t, J=7.1Hz), 2.09-2.18(2H, m), 2.50(2H, t, J=7.2 Hz), 3.77(3H, s), 4.05-4.15(4H,m), 6.90(1H, d, J=9.1), 7.08(1H, dd, J=9.1, 3.2 Hz), 7.30(1H, d, J=3.2Hz), 10.43(1H, s). IR(neat, cm⁻¹): 1731, 1683, 1496, 1218.

Reference Example 4 Ethyl 5-(2-Formyl-4-methoxyphenoxy)pentanoate

Colorless oil, yield 99%. ¹H-NMR(CDCl₃, δ, 300 MHz) 1.21(3H, t, J=7.1Hz), 1.80-1.87(4H, m), 2.37(2H, t, J=7.1 Hz), 3.77(3H, s), 4.01-4.14(4H,m), 6.89(1H, d, J=9.lHz), 7.08(1H, dd, J=9.1, 3.2 Hz), 7.29(1H, d, J=3.2Hz), 10.44 (1H, s). IR(neat, cm⁻¹): 1731, 1683, 1496, 1218.

Preparation of 2-formyl-N-methylaniline Derivatives in General ReferenceExample 5 5-(4-Bromo-2-formyl-N-methylanilino)pentanoic Acid

A suspension of 1-methyl-2-piperidone (5.0 g) in 4N sodium hydroxide(22.1 ml) was heated and stirred for 8.5 hours under reflux. After thesuspension was cooled to room temperature, conc. hydrochloric acid (7.4ml) was added. A solution of sodium carbonate (9.4 g) and5-bromo-4-fluorobezaldehyde (4.5 g) in DMSO (74 ml) was added, and theresulting mixture was stirred for 1.5 hours under reflux. The mixturewas allowed to cool to room temperature, and adjusted to pH of about 3.3with 6N hydrochloric acid. After extraction with ethyl acetate, theorganic layer was washed with saturated salt water, dried over anhydroussodium sulfate, and concentrated. The precipitated crystal obtained wasredissolved in isopropylether [IPE] (20 ml) under heating, and thesolution was allowed to cool to room temperature, and stirred for 1 hourat 0° C. The crystal obtained was filtered and washed with IPE. Dryingunder reduced pressure (40° C., 1 hour) gave yellow crystal of5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid (4.0 g, yield 57%).

mp. 72-73° C. ¹H-NMR (CDCl₃, δ, 300 MHz): 1.61-1.69(4H, m), 2.36(2H, t,J=6.7 Hz), 2.87(3H, s), 3.13(2H, t, J=6.9 Hz), 6.97(1H, d, J=8.8 Hz),7.54(1H, dd, J=8.8, 2.5 Hz), 7.86(1H, d, J=2.5 Hz), 10.17(1H, s). Anal.Calcd for C₁₃ H₁₆ NO₃ Br: C,49.70; H,5.13; N,4.46; Br,25.43, Found:C,49.75; H,5.16; N,4.45; Br,25.40. IR(KBr, cm⁻¹): 1731, 1648.

Compounds below in [REFERENCE EXAMPLE 6] to [Reference EXAMPLE 8] wereprepared according to a method similar to that of [REFERENCE EXAMPLE 5].

Reference Example 6 5-(2-Formyl-N-methylanilino)pentanoic Acid

Yellow oil, yield 37%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.64-1.73(4H, m),2.38(2H, t, J=6.7 Hz), 2.90(3H, s), 3.17(2H, t, J=6.9 Hz), 7.04-7.13(2H,m), 7.50(1H, dd, J=1.7, 5.5 Hz), 7.80(1H, dd, J=1.7, 7.7 Hz), 10.28(1H.s). IR(neat, cm⁻¹): 1708, 1683.

Reference Example 7 5-(2-Formyl-4-nitro-N-methylanilino)pentanoic Acid

Yellow crystal, yield 93%. mp. 107-108° C. ¹H-NMR(CDCl₃, δ, 300 MHz):1.60-1.67(2H, m), 1.75-1.81(2H, m), 2.38(2H, t, J=6.7 Hz), 2.90(3H, s),3.43(2H, t, J=7.4 Hz), 6.98(1H, d, J=9.4), 8.20(1H, dd, J=9.4, 2.8 Hz),8.58(1H, d, J=2.8 Hz), 9.67(1H, s). IR (KBr, cm⁻¹): 1704, 1677, 1598,1324, 1307.

Reference Example 8 6-(4-Bromo-2-formyl-N-methylanilino)hexanoic Acid

Yellow crystal, yield 80%. mp. 95-96° C. ¹H-NMR(CDCl₃, δ, 300 MHz):1.27-1.32(2H, m), 1.54-1.66(4H, m), 2.31(2H, t, J=7.4 Hz), 2.83(3H, s),3.08(2H, t, J=7.5 Hz), 6.93(1H, d, J=8.8 Hz), 7.50(1H, dd, J=8.8, 2.5Hz), 7.83(1H, d, J=2.5 Hz), 10.12(1H, s). Anal. Calcd for C₁₄ H₁₈ NO₃Br: C,51.23; H,5.53; N,4.27; Br,24.35. Found: C,51.25; H,5.54; N,4.21;Br,24.48. IR (KBr, cm⁻¹): 1720, 1644.

Preparation of 2-formyl-N-benzylaniline Derivatives in General ReferenceExample 9 5-(4-Bromo-2-formyl-N-benzylanilino)pentanoic Acid

To a solution of benzaldehyde (6.0 g) in methanol (80 ml),4-aminobutyric acid (6.6 g) and 1N sodium hydroxide (56.5 ml) wereadded. 20% Pd—C(wet, 0.6 g) was added to the reaction apparatus whichwas previously purged with an argon gas. Subsequently, the apparatus wasfilled with a hydrogen gas, and the solution was stirred at roomtemperature overnight. Pd—C was filtered off and washed with methanol.To the filtrate was added 6N hydrochloric acid (9.4 ml), and thesolvents were evaporated. Subsequently, sodium carbonate (12.0 g) andDMSO/water (57 ml/37 ml) were added to the residue, and the resultingmixture was heated under reflux with dropwise addition of a solution of5-bromo-4-fluorobenzaldehyde (5.7 g) in DMSO (17 ml), and stirredfurther for 5 hours. After cooled to room temperature, the solution wasadjusted to pH of about 3.5 by addition of 6N hydrochloric acid. Afterextraction with ethyl acetate, the organic layer was washed withsaturated salt water, dried over anhydrous sodium sulfate, andconcentrated. The concentrate was purified by silica gel columnchromatography (n-hexane/ethyl acetate=4/1) and subsequent concentrationof the appropriate eluate gave yellow oil of5-(4-bromo-2-formyl-N-benzylanilino)pentanoic acid (7.4 g, yield 61%).

¹H-NMR(CDCl₃, δ, 300 MHz): 1.52-1.65(4H, m), 2.27-2.35(2H, m),3.08-3.15(2H, m), 4.31(2H, s), 7.01(1H, d, J=8.7 Hz), 7.16-7.36(5H, m),7.57(1H, dd, J=8.7, 2.4 Hz), 7.92(1H, d, J=2.4 Hz), 10.36(1H, s).EI-MS(M*): 391.

IR(neat, cm⁻¹): 1708, 1683.

A compound below in [REFERENCE EXAMPLE 10] was prepared according to amethod similar to that of [REFERENCE EXAMPLE 9].

Reference Example 10 5-(4-Bromo-2-formyl-N-benzylanilino)heptanoic Acid

Yellow oil, yield 27%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.21-1.26(4H, m),1.46-1.56(4H, m), 2.27(2H, t, J=7.4 Hz), 3.05(2H, t, J=7.5 Hz), 4.26(2H,s), 6.97(1H, d, J=8.7 Hz), 7.13-7.28(5H, m), 7.51(1H, dd, J=8.7, 2.5Hz), 7.87(1H, d, J=2.5 Hz), 10.30(1H, s). IR (neat, cm⁻¹): 1706, 1683.

Cyclization Reactions in General (Method A)

Example 1 2,3-Dihydro-1-benzoxepin-4-carboxylic acid ethylester

To a solution of 4-(2-formylphenoxy)butyric acid ethylester (2.4 g) indiethyl carbonate (24 ml), a solution of 20% sodium ethoxide in ethanol(4.lg) was added at room temperature, and the solution was stirred at50° C. for 1 hour. The solution was allowed to cool to room temperature,and neutralized with 1N hydrochloric acid. After ethyl acetateextraction, the organic layer was washed with saturated salt water,dried over anhydrous sodium sulfate, and concentrated. The concentratewas purified by silica gel column chromatography (n-hexane/ethylacetate=10/1) and concentration of the appropriate eluate gave colorlessoil of 2,3-dihydro-l-benzoxepin-4-carboxylic acid ethylester (1.3 g,yield 61%).

¹H-NMR(CDCl₃, δ, 300 MHz): 1.36(3H, t, J=7.1 Hz), 2.97-3.00(2H, m),4.26-4.31(4H, m), 6.96-7.04(2H, m), 7.21-7.27(1H, m), 7.32-7.35(1H, m),7.58(1H, s). IR (neat, cm⁻¹): 1700, 1249.

Reference Example 11 2,3-Dihydro-1-benzoxepin-4-carboxylic AcidEthylester

To a solution of 4-(2-formylphenoxy)butyric acid ethylester (2.4 g) inTHF (24 ml), potassium t-butoxide (1.2 g) was added at room temperature,and the mixture was stirred at 50° C. for 2 hours. The solution wasallowed to cool to room temperature, and neutralized with 1Nhydrochloric acid. After ethyl acetate extraction, the organic layer waswashed with saturated salt water. The organic layer was subjected toHPLC analysis.

The results of quantitative analyses: 4-(2-formylphenoxy)butyric acidethylester (0.1 g, yield 4%), 4-(2-formylphenoxy)butyric acid (0.3 g,yield 14%), 2,3-dihydro-1-benzoxepin-4-carboxylic acid ethylester (0.4g, yield 17%), 2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.3 g, yield15%).

Compounds below in [EXAMPLE 2] to [EXAMPLE 4] were prepared according toa method similar to that of [EXAMPLE 1].

Example 2 7-Bromo-2,3-dihydro-1-benzoxepin-4-carboxylic Acid Ethylester(Method A)

White crystal, yield 34%. mp. 85-86° C. ¹H-NMR(CDCl₃, δ, 300 MHz):1.34(3H, t, J=7.1 Hz), 2.92-2.97(2H, m), 4.19-4.25(4H, m), 6.82(1H, d,J=8.6 Hz), 7.28(1H, dd, J=8.6, 2.4 Hz), 7.42(1H, d, J=2.4 Hz), 7.43(1H,s).

Example 3 7-Methoxy-2,3-dihydro-1-benzoxepin-4-carboxylic AcidEthylester (Method A)

White crystal, yield 82%. mp. 62-63° C. ¹H-NMR(CDCl₃, δ, 300 MHz):1.32(3H, t, J=7.1 Hz), 2.92-2.95(2H, m), 3.76(3H, s), 4.17-4.28(4H, m),6.77-6.81(2H, m), 6.87(1H, dd, J=l.6, 7.4 Hz), 7.49(1H, s).

Example 4 8-Methoxy-3,4-dihydro-2H-1-benzoxocin-5-carboxylic AcidEthylester (Method A)

Colorless oil, yield 11%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.44(3H, t, J=7.1Hz), 1.82-1.88(2H, m), 2.66-2.70(2H, m), 3.86(3H, s), 4.24-4.39(4H, m),6.77 (1H, d, J=3.0 Hz), 6.92(1H, dd, J=3.0, 8.9 Hz), 7.02(1H, d, J=8.9Hz), 7.70(1H, s). IR (neat, cm⁻¹): 1704, 1496, 1243.

Cyclization Reactions in General (Method B)

Example 5 8-Bromo-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicAcid Methylester

To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid (3.0g) in DMF(8 ml), potassium carbonate (1.6 g) and a solution of methyliodide/DMF (1.6 g/2 ml) were added at room temperature, and theresulting mixture was stirred for 2 hours. Ethyl acetate and water wereadded to the mixture, and the organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, and concentrated to giveyellow oil of 5-(4-bromo-2-formyl -N-methylanilino)pentanoic acidmethylester (3.0 g, yield 97%).

¹H-NMR(CDCl₃, δ, 300 MHz): 1.58-1.64(4H, m), 2.28(2H, t, J=6.8 Hz),2.83(3H, s), 3.09(2H, t, J=6.8 Hz), 3.63(3H, s), 6.95(1H, d, J=8.8 Hz),7.51(1H, dd, J=8.8, 2.4 Hz), 7,83(1H, d, J=2.4 Hz), 10.14(1H, s). FAB-MS([M+Na]⁺): 350. IR(neat, cm⁻¹): 1735, 1681.

To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoic acidmethylester (3.0 g) in dimethyl carbonate (40 ml), a solution of 28%sodium methoxide in methanol (2.3 g) was added at room temperature, andthe resulting mixture was stirred at 50° C. for 2 hours. The mixture wasallowed to cool to room temperature, and neutralized with 1Nhydrochloric acid. After ethyl acetate extraction, the organic layer waswashed with saturated salt water, dried over anhydrous sodium sulfate,and concentrated. The concentrate was purified by silica gel columnchromatography (h-hexane/ethyl acetate=10/1) and the appropriate eluatewas concentrated. The precipitated crystal was washed with IPE andcollected by filtration. Drying under reduced pressure (40° C., 1 hour)gave yellow crystal of8-bromo-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acidmethylester (0.9 g, yield 31%). mp. 88-89° C. ¹H-NMR(CDCl₃, δ, 300 MHz):1.44(2H, m), 2.54(2H, t, J=6.2 Hz), 2.87(3H, s), 3.42(2H, t, J=5.6 Hz),3.78(3H, s), 6.56(1H, d, J=6.0 Hz), 7.19-7.23(2H, m), 7.68(1H, s). Anal.Calcd for C₁₄ H₁₆ NO₂ Br: C,54.21; H,5.20; N,4.52; Br,25.76. Found:C,54.19; H,5.29; N,4.37; Br,25.74. IR(KBr, cm⁻¹): 1689, 1189.

Compounds below in [EXAMPLE 6] to [EXAMPLE 9] were prepared according toa method similar to that of [EXAMPLE 5].

Example 6 1-Methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic AcidMethylester (Method B)

5-(2-Formyl-N-methylanilino)pentanoic acid methylester Yellow oil, yield99%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.58-1.68(4H, m), 2.30(2H, t, J=6.8),2.86(3H, s), 3.12(2H, t, J=6.8 Hz), 3.64(3H, s), 7.01-7.10(2H, m),7.46(1H, dt, J=1.7, 7.3 Hz), 7.76(1H, dd, J=1.7, 7.7 Hz), 10.25(1H, s).IR (neat, cm⁻¹): 1735, 1685, 1159.

1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic Acid Methylester

Yellow crystal, yield 30%. mp. 80-82° C. ¹H-NMR(CDCl₃, δ, 300 MHz):1.42-1.50(2H, m), 2.57(2H, t, J=6.2 Hz), 2.90(3H, s), 3.45(2H, t, J=5.4Hz), 3.79(3H, s), 6.62-6.73(2H, m), 7.11-7.22(2H, m), 7.80(1H, s). Anal.Calcd for C,4 H₁ NO₂: C,72.70; H,7.41; N,6.06. Found: C,73.00; H,7.65;N,6.06. IR (KBr, cm⁻¹): 1685, 1189.

Example 7 1-Benzyl-8-bromo-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicAcid Methylester (Method B)5-(4-Bromo-2-formyl-N-benzylanilino)pentanoic Acid Methylester

Yellow oil, yield 100%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.57-1.60(4H, m),2.27(2H, t, J=6.7), 3.12(2H, t, J=6.6 Hz), 3.66(3H, s), 4.31(2H, s),7.01(1H, d, J=8.7), 7.17-7.33(5H, m), 7.56(1H, dd, J=8.7, 2.5 Hz),7.92(1H, d, J=2. 5 Hz), 10.35 (1H,s). EI-MS(M+): 403. IR (neat, cm⁻¹):1735, 1683.

1-Benzyl-8-bromo-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic AcidMethylester

Yellow oil, yield 76%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.44-1.50(2H, m),2.59(2H, t, J=6.lHz), 3.50(2H, t, J=5.3 Hz), 3.81(3H, s), 4.45(2H, s),6.50(1H, d, J=9.0), 7.09-7.39(7H, m), 7.75(1H, s). EI-MS(M⁺): 385.

IR(neat, cm⁻¹): 1704, 1495, 1087.

Example 89-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazonin-6-carboxylic AcidMethylester (Method B) 6-(4-Bromo-2-formyl-N-methylanilino)hexanoic AcidMethylester

Yellow oil, yield 98%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.20-1.30(2H, m),1.51-1.61(4H, m), 2.24(2H, t, J=7,4), 2.81(3H, s), 3.05(2H, t, J=6.6Hz), 3.61(3H, s), 6.91(1H, d, J=8.8 Hz), 7.47(1H, dd, J=8.8, 2.3 Hz),7.80(1H, d, J=2.3 Hz), 10.10(1H, s). FAB-MS([M+Na]⁺): 364. IR(neat,cm⁻¹): 1735, 1681.

9-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazonin-6-carboxylic AcidMethylester

Yellow oil, yield 18%. ¹H-NMR-(CDCl₃, δ, 300 MHz): 1.67-1.77(2H, m),1.87-1.96(2H, m), 2.30(2H, t, J=6.9 Hz), 2.76(3H, s), 3.12(2H, t, J=6.9Hz), 3.77(3H, s), 6.70(1H, d, J=6.4 Hz), 7.19-7.22(2H, m), 7.60(1H, s).EI-MS(M⁺):323. IR(neat, cm⁻¹): 1708, 1494.

Cyclization Reactions in General (Method C)

Example 9 8-Nitro-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylicAcid Methylester

To a solution of 5-(2-formyl-4-nitro-N-methylanilino)pentanoic acid (3.0g) in DMF (8.1 ml), potassium carbonate (1.6 g) and a solution of methyliodide/DMF (1.8 g/1 ml) were added at room temperature, and theresulting mixture was stirred further for 2 hours. To the mixture,dimethyl carbonate (18 ml) and subsequently a solution of 28% sodiummethoxide in methanol (5.0 g) were added and the resulting mixture wasstirred at 50° C. for 2.5 hours. The mixture was allowed to cool to roomtemperature, and neutralized with 1N hydrochloric acid. After ethylacetate extraction, the organic layer was washed with saturated saltwater, dried over anhydrous sodium sulfate, and concentrated. Theconcentrate was redissolved in hot isopropyl alcohol [IPA], and thesolution was allowed to cool to room temperature, stirred at roomtemperature further for 1 hour, and at ice temperature for 0.5 hours.The precipitated crystal was collected by filtration, and washed withIPA. The crystal was purified by silica gel column chromatography(n-hexane/ethyl acetate=2/1 to 1/1), and subsequent concentration of theappropriate eluate gave yellow crystal of8-nitro-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acidmethylester (2.3 g, yield 78%). mp. 127-129° C. ¹H-NMR(CDCl₃, δ, 300MHz): 1.38-1.72(2H, m), 2.35-2.80(2H, m), 3.02(3H, s), 3.42-3.85(2H, m),3.80(3H, s), 6.65(1H, d, J=9.4 Hz), 7.80(1H, s), 7.99-8.06(2H,m). Anal.Calcd for C₁₄ H₁₆ N₂ O₂: C,60.86; H,5.84; N,10.14. Found: C,60.79;H,5.81; N,9.98. IR (KBr, cm⁻¹): 1708, 1255, 119].

A compound below in [EXAMPLE 10] was prepared according to a methodsimilar to that of [EXAMPLE 9].

Example 101-Benzyl-10-bromo-1,2,3,4,5,6-hexahydro-1-benzazecin-7-carboxylic AcidMethylester (Method C)

Yellow oil, yield 6%. ¹H-NMR(CDCl₃, δ, 300 MHz): 1.24-1.29(2H, m),1.44-1.50(2H, m), 1.57-1.63(2H, m), 2.13(2H, t, J=6.5 Hz), 2.89(2H, t,J=6.2 Hz), 3.48(3H, s), 3.90(2H, s), 7.02(1H, d, J=8.6 Hz),7.10-7.25(6H, m), 7.37(1H, dd, J=8.6, 2.4 Hz), 7.48(1H, s). IR(KBr,cm⁻¹): 1712, 1279, 1232.

Reference Example 11 Preparation of4′-ethoxy-4-hydroxy-1,1′-biphenyl-3-carbaldehyde

To a suspension of magnesium (0.5 g) in THF (7 ml), a solution of1-bromo-4-ethoxybenzene (4.0 g) in THF (2.5 ml) was added slowly at roomtemperature under an argon atmosphere, and the resulting solution wasstirred for 1 hour. Subsequently, a solution of trimethoxyborane (2.1 g)in THF (2.5 ml) was added dropwise at −10 to 10° C., and after furtheraddition of THF (7 ml), the reaction mixture was stirred at the sametemperature for 1 hour. The reaction mixture was allowed to warm to roomtemperature and tetrakistriphenylphosphine palladium (115mg),5-bromo-2-hydroxybenzaldehyde (2.0 g) and an aqueous solution oftripotassium phosphate (11.1 g) in water (15 ml) were added, and theresulting mixture was stirred under reflux for 1 hour. After the mixturewas allowed to cool to room temperature, 6N hydrochloric acid (20 ml)was added dropwise, and then toluene(20 ml) was added. After separation,the aqueous phase was further extracted with toluene (30 ml). Theorganic layers were combined and washed with aqueous 10% sodium chloridesolutions (10 ml×3), dried over anhydrous magnesium sulfate andconcentrated. The concentrate was purified by silica gel chromatography(n-hexane/ethyl acetate=6/1), and the appropriate eluate wasconcentrated. Diisopropylether (15 ml) was added to the concentrate andthe resulting mixture was heated under reflux, and then allowed to coolto room temperature. n-Hexane (15 ml) was added to the solution, andstirred at room temperature for 1 hour and at 0° C. for 0.5 hour. Theprecipitated crystal was collected by filtration and washed withdiisopropylether/n-hexane (1/1.4 ml) which was previously cooled to 0 to5° C. Drying under reduced pressure (room temperature, 2 hours) gaveyellow crystal of the title compound (1.8 g, yield 73%).

mp. 94-95° C.

Anal Calcd. for C₁₅ H₁₄ O₃: C,74.36; H,5.82. Found: C,74.61; H,5.80.

IR(KBr, cm⁻¹): 1660, 1473, 1276, 1245, 1047, 831.

¹H-NMR(CDCl₃, 300 MHz) δ 1.44(3H, t, J=7.0 Hz), 4.07(2H, q, J=7.0 Hz),6.96(2H, dd, J=1.9, 6.7 Hz), 7.04(1H, d, J=8.4 Hz), 7.45(2H, dd, J=1.9,6.7 Hz), 7.68-7.77(2H, m), 9.95(1H, s), 10.95(1H, s).

Reference Example 12 Preparation of4-[(4′-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxy]butyric acid ethylester

To a solution of 4′-ethoxy-4-hydroxy-1,1′-biphyenyl-3-carbaldehyde(1.0g), and 4-bromobutyric acid ethylester (0.9 g) in DMF (5 ml) was addedpotassium carbonate (1.1 g) at room temperature, and the solution wasstirred at room temperature for 14 hours, and at 50° C. for 3 hours.After the solution was allowed to cool to room temperature, water (10ml) was added, and extracted with ethyl acetate (30 ml). The organiclayer was washed with water (10 ml×3), and concentrated. To theconcentrate was added diisopropylether (14 ml), and the resultingmixture was heated under reflux and subsequently cooled to roomtemperature. The solution was further stirred at room temperature for 1hour, and at 0° C. for 1 hour. The precipitated crystal was collected byfiltration and washed with diisopropylether (3 ml) which was previouslycooled to 0 to 5° C. Drying under vacuum (room temperature, 2 hours)gave white crystal of the title compound (1.3 g, yield 91%). mp. 69-70°C.

Anal Calcd. for C₂₁ H₂₄ O₅: C,70.77; H,6.79. Found: C,70.91; H,7.08.

IR (KBr, cm⁻¹) 1683, 1606, 1471, 1270, 1240, 1187, 1047. ¹H-NMR(CDCl₃,300 MHz) δ 1.26(3H, t, J=7.1 Hz), 1.43(3H, t, J=7.0 Hz), 2.18-2.25(2H,m), 2.56(2H, t, J=7.1 Hz), 4.04-4.20(6H, m), 6.94(2H, dd, J=1.9, 6.7Hz), 7.03(1H, d, J=8.7 Hz), 7.47(2H, dd, J=1.9, 6.7 Hz), 7.72(1H, dd,J=8.7, 2.5 Hz), 8.02(1H, d, J=2.5 Hz), 10.53(1H, s).

Example 11 7-(4-Ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-carboxylic AcidEthylester

To a solution of 4-[(41-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxylbutyricacid ethylester (0.50 g) in diethyl carbonate (5 ml) was added asolution of 20% sodium ethoxide in ethanol (0.57 g) at room temperature,and the mixture was then heated to 50° C. and stirred for 1 hour. Thesolution was neutralized with 1N hydrochloric acid, and extracted withethyl acetate. The organic layer was washed, and concentrated. Theconcentrate was purified by silica gel chromatography (n-hexane/ethylacetate=10/1) and subsequent concentration of the appropriate eluategave white crystal of the title compound (0.39 g, yield 82%).

mp. 128-129° C. Anal Calcd. for C₂₁ H₂₂ O₄: C,74.54; H,6.55. Found:C,74.32; H,6.46.

IR(KBr, cm⁻¹), 1702, 1496, 1251, 1213.

¹H-NMR(CDCl₃, 300 MHz) δ 1.37(3H, t, J=7.1 Hz), 1.44(3H, t, J=7.0 Hz),2.99-3.02(2H, m), 4.07(2H, q, J=7.0 Hz), 4.26-4.32(4H, m), 6.95(2H, dd,J=1.9, 6.7 Hz), 7.00(1H, d, J=8.4 Hz), 7.41-7.51(4H, m), 7.65(1H, s).

Industrial Applicability

The present invention provides a process suitable for mass productionwherein cyclic compounds can be produced safely through a short step.

1-18. (canceled)
 19. A compound represented by the formula: [formula]

[wherein, Z is an electron-withdrawing group; W is an optionallysubstituted ethylene or an optionally substituted vinylene and when theethylene or the vinylene has two substituent groups, said substituentgroups may be bound to each other to form an optionally substitutedring; R³ is a hydrogen atom or an optionally substituted hydrocarbongroup; and X″ is a divalent group having 4 or more atoms in thestraight-chain moiety thereof] or a salt thereof.